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It has been proposed that evaluation of alcoholic patients for liver transplantation should comprise a multidisciplinary program including medical, surgical, and psychiatric assessment. This article presents the outcome in 99 alcoholic persons evaluated from 1985 through 1989. Alcoholism was defined as alcohol dependence or abuse according to the DSM-III-R. Forty-five patients (43%) were considered suitable candidates and underwent transplantation. Actuarial survival in this group was 78% and 73% at 12 and 24 months, respectively, and did not differ from that observed in nonalcoholic recipients. Return to alcohol use after transplantation has been documented in 5 persons, 2 of whom have had episodes of uncontrolled drinking. Of 54 patients not selected for transplantation, 17 were considered too well and suitable for alternative therapy. Actuarial survival was 93% at 12 and 18 months but declined to 59% at 24 months. Nineteen patients were medically unsuitable and had very poor survival; survival was 35% at 3 months and 0% at 12 months. Seventeen patients were not selected on psychiatric grounds. Actuarial survival in this group (65% at 12 months, 43% at 18 months) was significantly less than that in alcoholics with transplants (P less than 0.05). There were no differences in age, sex ratio, degree of hepatic dysfunction, or duration of abstinence between alcoholics with transplants and those considered psychiatrically unsuitable. It was concluded that liver transplantation is successful in selected patients with alcoholic cirrhosis, that patients who are not selected because they are "too well" need continuing surveillance as a significant decline in survival can occur 18-24 months after initial evaluation and, finally, that patients not selected on psychiatric grounds have a significantly worse survival rate than those with transplants.

Ethanol (10 or 15% in the drinking water) was found to increase the amount of collagen in the livers of rats receiving a cirrhogenic diet. This effect of ethanol was most striking in the animals receiving 10% ethanol. Ethanol lowered the amount of labeled proline incorporated into hydroxyproline and, therefore, into collagen. The amount of labeled hydroxyproline remaining in the liver 7 days after injection was greater in the rats receiving 10% ethanol than in the pair-fed controls. A net increase in collagen deposition attributable to ethanol was associated with lowered rate of collagen synthesis. The main action of ethanol in increasing the rate of collagen deposition, therefore, must be inhibition of collagen breakdown.

The isolated perfused liver of the cirrhotic rat produces greater quantities of ammonia from endogenous sources or from added alanine than do control livers. It also fails to take up ammonia. In these cirrhotic livers ethanol increases ammonia production in the presence of alanine. When cirrhotic rats had received a normal diet for 10 days before perfusion, the output of ammonia from endogenous sources and from added alanine is partially restored to normal. The addition of ethanol in the presence of alanine to the perfusate of these cirrhotic livers then results in an increased rate of production of glutamine rather than of ammonia. A normal diet given these cirrhotic animals restores the uptake of ammonia to that seen in the control animals but, unlike the normal animals, the addition of ornithine increases neither the uptake of ammonia nor the output of urea. In the normal animals this effect of ornithine on the uptake of ammonia is abolished by ethanol. It is concluded that cirrhotic rat liver is a source of endogenous ammonia and that the magnitude of that contribution is modified by diet and by ethanol.

Chronic nutritional injury was induced in rats by a high-fat, lipotrope-deficient diet. The hepatoprotective effect of 16,16-dimethyl prostaglandin E2 on the deposition of collagen and fat was assessed by histological evaluation and measurement of hydroxyproline. Dose-response studies established that optimal protection was achieved by the twice daily administration of 16,16-dimethyl prostaglandin E2 at 100 micrograms per kg (subcutaneous) or 250 micrograms per kg (oral). 16,16-Dimethyl prostaglandin E2 and a crystalline analog [(p-acetamidobenzamido)phenyl ester of 16,16-dimethyl prostaglandin E2 significantly delayed both the deposition of collagen and the increase in hepatic hydroxyproline content. There was an excellent correlation between the histological assessment of collagen and the biochemical measurement of hydroxyproline. These data provide a rationale for the evaluation of prostaglandins in the treatment of human liver disease.

Liver transplantation is a highly successful therapy for liver diseases that were previously debilitating and often fatal within a few months. One-year actuarial patient survival for our first 162 patients is 74.7%. Our results have improved since the inception of the program despite the fact that the indications have been extended to higher risk patients such as those with fulminating hepatitis or thrombosed portal veins. The prognosis following transplantation for each specific indication needs to be defined, especially for hepatitis, alcoholic cirrhosis and individual cancers. We believe that a more conservative approach to immunosuppression, close attention to intravenous and enteral nutrition, and aggressive treatment of complications (including prompt reoperation when indicated) have been important improvements in our management practices.

To determine whether a serum parameter of collagen metabolism, serum procollagen type III peptide, correlated with hepatic collagen in a model of diet-induced fibrosis, rats were fed a control or cirrhogenic diet for 6 months and treated with either subcutaneous vehicle or the hepatoprotective prostaglandin 16,16-dimethyl prostaglandin E2 (100 micrograms per kg) twice daily. Pair-fed rats from each group were killed after 2, 4 or 6 months. The value of serum procollagen type III peptide to body weight integrated over time (Kt) correlated linearly with hepatic hydroxyproline content (r = 0.97) at killing time t. Good correlations were also seen between Kt and histopathological assessment of aniline blue-stainable collagen (r = 0.93) and between the histopathology and hydroxyproline content (r = 0.97). Rats receiving 16,16-dimethyl prostaglandin E2 had lower values of all three parameters compared to rats receiving vehicle, confirming the previously demonstrated hepatoprotective effect of 16,16-dimethyl prostaglandin E2. The excellent correlation between Kt and the two other traditional parameters of hepatic collagen suggest that sequential measurements of serum procollagen type III peptide can be used to predict alterations in liver collagen deposition in rats.

Bilateral lesions placed in the pontiene tegmentum resulted in episodes of paradoxical sleep in which the characteristic atonia of that sleep stage was absent in six cats. Following each period of synchronized sleep, in which the degree of muscle tone of the dorsal cervical muscles gradually diminished, cats with such lesions would slowly raise their heads, move their limbs at all joints, make several attempts to rise and eventually leap violently. During such episodes they were unresponsive to strong lights, touching and mild pinching. Only sound would arouse them. This behavior appeared as early as the 2nd postoperative day, the 1st day of recording. Such episodes supplanted normal paradoxical sleep with atonia and lasted unchanged for as long as 6 months in one cat until it was killed while still in good health. Complete recovery of atonia was observed in one cat after 3 weeks. Either no recovery or else eventual recovery to excessively active periods of paradoxical sleep while remaining recumbent characterized the sleep of the other four. The conclusion drawn from these experiments and from a review of the literature is that the hypotheses stating that the locus coeruleus or other isolated nuclei of the pons are specifically concerned with the initiation of paradoxical sleep are not clearly supported by available evidence.

The effect of 16,16 dimethyl prostaglandin E2 (DMPG) on fibrogenesis was studied in slices from normal and fibrotic rat liver. Rats received a cirrhogenic diet for seven months; supplemented controls received a diet with the deficient nutrients restored. Slices from fibrotic livers incorporated more 14C-proline and produced more 14C-hydroxyproline in TCA precipitable proteins than slices from control livers. DMPG (10(-10) M) decreased the incorporation of labeled proline and the synthesis of labeled hydroxyproline in slices from fibrotic livers to the same extent, suggesting that DMPG did not affect the hydroxylation of proline per se. The magnitude of the DMPG induced decrease in labeled proline incorporation correlated with the hydroxyproline content in the liver (i.e. with increasing fibrosis there was a greater effect of DMPG: while in control rat liver slices, DMPG had no effect). DMPG did not change the size of the proline pool, its specific activity, or the activity of proline oxidase. We conclude that under these conditions of enhanced fibrogenesis, DMPG decreases the formation of collagen in vitro, possibly by lowering the incorporation of proline into collagen precursors. This may explain, at least in part, the inhibition of fibrogenesis by DMPG in vivo.